Background Epilepsy is a chronic neurological disorder, which has potentially adverse cognitive and psychosocial consequences. Objectives To assess the quality of life (QOL) of adolescents with epilepsy (AWE) and their families and also factors affecting it, related to both the disease burden and the antiepileptic drug. Patients and methods A cross-sectional study was done on 217 AWE and one parent each. Sociodemographic and disease-related data were collected. Patients completed the QOL in epilepsy questionnaire (AD-48) and pediatric epilepsy side effects questionnaire. The parents completed impact of epilepsy on QOL questionnaire. Results Mean patients’ age was 14.33 years old, having disease since a mean duration of 6.62 years. Overall, 59.5% of them received polytherapy, with 37.3% having received new line of drugs. Approximately one-third of them had partial seizures. Half of them had one or two attacks per month. The mean total QOL score was 55.91±5.55. The largest percentage of parents reported that epilepsy had worse effects on their attitude, family change, general well-being, and adolescents’ QOL. There are significant relationships between QOL and mother education, age group, disease duration, seizures frequency, and type and line of antiepileptic drugs. There are significant negative correlations between all pediatric epilepsy side effects questionnaire domains and QOL. Conclusions Epilepsy had adverse effect on AWE and their families. Illiterate mothers, older, increasing duration, seizure frequency, generalized type, and being on old or combined drug regimens are the predictors of poor QOL. Keywords: adolescents, epilepsy, predictor, quality of life